Phthalic Acid Esters: Natural Sources and Biological Activities
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toxins Review Phthalic Acid Esters: Natural Sources and Biological Activities Ling Huang 1,2,†, Xunzhi Zhu 3,†, Shixing Zhou 1,4, Zhenrui Cheng 1, Kai Shi 1,4, Chi Zhang 5,* and Hua Shao 1,2,4,* 1 State Key Laboratory of Desert and Oasis Ecology, Xinjiang Institute of Ecology and Geography, Chinese Academy of Sciences, Urumqi 830011, China; [email protected] (L.H.); [email protected] (S.Z.); [email protected] (Z.C.); [email protected] (K.S.) 2 Research Center for Ecology and Environment of Central Asia, Xinjiang Institute of Ecology and Geography, Chinese Academy of Sciences, Urumqi 830011, China 3 Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China; [email protected] 4 University of Chinese Academy of Sciences, Beijing 100049, China 5 Shandong Provincial Key Laboratory of Water and Soil Conservation and Environmental Protection, College of Resources and Environment, Linyi University, Linyi 276000, China * Correspondence: [email protected] (C.Z.); [email protected] (H.S.) † These authors contributed equally to this work. Abstract: Phthalic acid esters (PAEs) are a class of lipophilic chemicals widely used as plasticizers and additives to improve various products’ mechanical extensibility and flexibility. At present, synthesized PAEs, which are considered to cause potential hazards to ecosystem functioning and public health, have been easily detected in the atmosphere, water, soil, and sediments; PAEs are also frequently discovered in plant and microorganism sources, suggesting the possibility that they might be biosynthesized in nature. In this review, we summarize that PAEs have not only been identified in the organic solvent extracts, root exudates, and essential oils of a large number of different plant species, but also isolated and purified from various algae, bacteria, and fungi. Dominant PAEs identified from natural sources generally include di-n-butyl phthalate, diethyl phthalate, dimethyl phthalate, di(2-ethylhexyl) phthalate, diisobutyl phthalate, diisooctyl phthalate, etc. Further studies Citation: Huang, L.; Zhu, X.; Zhou, reveal that PAEs can be biosynthesized by at least several algae. PAEs are reported to possess S.; Cheng, Z.; Shi, K.; Zhang, C.; Shao, H. Phthalic Acid Esters: Natural allelopathic, antimicrobial, insecticidal, and other biological activities, which might enhance the Sources and Biological Activities. competitiveness of plants, algae, and microorganisms to better accommodate biotic and abiotic stress. Toxins 2021, 13, 495. https://doi.org/ These findings suggest that PAEs should not be treated solely as a “human-made pollutant” simply 10.3390/toxins13070495 because they have been extensively synthesized and utilized; on the other hand, synthesized PAEs entering the ecosystem might disrupt the metabolic process of certain plant, algal, and microbial Received: 13 June 2021 communities. Therefore, further studies are required to elucidate the relevant mechanisms and Accepted: 14 July 2021 ecological consequences. Published: 16 July 2021 Keywords: phthalic acid esters; natural sources; biological activity; di-n-butyl phthalate; di(2- Publisher’s Note: MDPI stays neutral ethylhexyl) phthalate with regard to jurisdictional claims in published maps and institutional affil- Key Contribution: PAEs detected in the environment are mostly considered human-made pollutants; iations. however, our review provides evidence that they can actually be biosynthesized by certain species of plants, algae, bacteria, fungi, etc., to enhance the competitiveness of their hosts. Their biological activities have the potential to be explored and utilized further. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article 1. Introduction distributed under the terms and conditions of the Creative Commons Phthalic acid esters (PAEs) are common plasticizers added to polymeric materials to Attribution (CC BY) license (https:// improve their flexibility and workability [1]. PAEs have been widely used in numerous con- creativecommons.org/licenses/by/ sumer products, including cosmetics, food packaging, building materials, medical supplies, 4.0/). home furnishings, etc., due to their characteristic properties, such as their good insulation, Toxins 2021, 13, 495. https://doi.org/10.3390/toxins13070495 https://www.mdpi.com/journal/toxins Toxins 2021, 13, 495 2 of 17 high strength, excellent corrosion resistance, low cost, and ease of fabrication [2–4]. The current global production of PAEs is estimated at 300 million tons, and it is expected to reach 500 million tons by 2050, most of which will be single-use products [5]. Moreover, China has become the world’s largest producer, consumer, and importer of plasticizers, accounting for nearly 42% of the world’s consumption in 2017 [6]. As one of the most abundantly produced phthalates, di(2-ethylhexyl) phthalate accounts for one-third and 80% of the phthalates made in the European Union and China, respectively [7]. With such extensive application of phthalate-containing products, PAEs have attracted increas- ing attention as environmental and biomedical pollutants, which may invisibly enter the human body through airborne transmission, skin contact, and food chain transmission, constituting potential health and ecological system threats [8]. In fact, a number of studies have been carried out to investigate the toxicity of PAEs on human beings and/or animals. Epidemiologic studies found that early phthalates exposure could induce significant neuro- developmental damage [9]. Some PAEs have been proven to possess reproductive and developmental toxicities to animals and are suspected of causing endocrine-disrupting effects to humans [10–12]. PAEs were also harmful to aquatic organisms. Di-n-butyl, diethyl phthalate, and their mixture were found to effectively activate zebrafish embryos’ antioxidant system and lead to immunotoxicity and neurotoxicity [13,14]. Zhao et al. (2014) reported that di-n-butyl and di(2-ethylhexyl) phthalate disrupted the antioxidant system of carps, meanwhile combined exposure to these two compounds exacerbated this change [15]. Up to now, most of the published literature has focused on the detection methods, pollution distribution, and toxicological hazards of PAEs. However, the natural sources of various PAEs are rarely studied. The first report of phthalic acid as a natural substance was conducted by Schmid and Karrer (1945) [16] and, since then, more than 50 differ- ent derivatives of PAEs have been reported from different taxonomic groups, including bacteria, actinomycetes, fungi, fern, higher plants, and even animals [17]. What remains unclear, however, is that in many cases, it is rather complicated to determine whether these compounds come from synthesized materials that later cause contamination of the air, water, or soil, or whether they may be produced by the plants and microorganisms themselves. The objective of this review is to summarize the plant and microorganism origin of PAEs so as to better understand their possible sources: Are they synthesized chemicals, or are they naturally occurring secondary metabolites? 2. Physicochemical Properties and Applications of PAEs Phthalic acid esters (dialkyl or alkyl aryl esters of 1,2-benzenedicarboxylic acid), usu- ally called PAEs, phthalate esters, or just phthalates, are a group of important derivatives of phthalic acids which are synthesized from phthalic anhydride and specific alcohols by Fischer esterification [18,19]. PAEs based on hydrogen bond and van der Waals force interconnection are hydrophobic compounds with log Kow ranging from 1.6 to 12 [20]. Most of the phthalate esters are colorless liquids with a low volatility, high boiling point, and poor solubility in water, but they are soluble in organic solvents and oils [8]. These esters’ general chemical structure consists of a rigid planar aromatic ring and two malleable nonlinear fatty side chains. The two side-chain groups can be the same or not, and there are approximately 30 types of different side chains, ranging from dimethyl phthalate to tridecyl ester [21]. Due to phthalate esters being widespread in the biosphere and potential hazards in relation to ecosystem functioning and public health, six PAEs have been listed as prior- ity pollutants by the United States Environmental Protection Agency and the European Union [20,22], including dimethyl phthalate, diethyl phthalate, di-n-butyl phthalate, butyl benzyl phthalate, di(2-ethylhexyl) phthalate, and di-n-octyl phthalate. These phthalate esters’ physicochemical properties and common applications are summarized in Table1 and Figure1. Toxins 2021, 13, x FOR PEER REVIEW 3 of 17 lower molecular weight, such as dimethyl phthalate, diethyl phthalate, and di-n-butyl phthalate, are widely used in cosmetics and personal care products; dimethyl phthalate and diethyl phthalate allow perfume fragrances to evaporate more slowly, making the scent linger longer, and a small amount of di-n-butyl phthalate can make nail polish chip-resistant. Di-n-butyl phthalate is also used in cellulose esters, printing inks, latex adhesives, and insect repellents [11,24]. Higher phthalate molecules, such as di(2-ethylhexyl) phthalate, diisononyl phthalate, and butyl benzyl phthalate, have a wide range of applications as plasticizers in the polymer industry to improve flexibility, workability, and general handling proper- ties, and about 80% of PAEs are used for this purpose [20,25]. The stability, fluidity